Homology Models of Melatonin Receptors: Challenges and Recent Advances

Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT(1) and MT(2). So far, a number of different MT(1) and MT(2) receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compounds will be commented upon.